Tanezumab Eases OA Pain, Safety Still an Issue

Action Points

The monoclonal antibody tanezumab, which targets nerve growth factor and is under development for the treatment of pain in conditions including osteoarthritis, was effective in a phase III clinical trial, but safety concerns persist.

Point out that the incidence of rapidly progressive OA was higher for the 10 mg tanezumab dose compared with NSAIDs, and rapidly progressive OA was more likely when tanezumab was given in combination with an NSAID.

The monoclonal antibody tanezumab, which targets nerve growth factor and is under development for the treatment of pain in conditions including osteoarthritis (OA), was effective in a phase III clinical trial, but safety concerns persist.

In 2010, the FDA imposed a "partial clinical hold" on the development program of tanezumab because of reports of numerous cases of suspected osteonecrosis that necessitated total joint replacements.

A subsequent adjudication committee examination of the relevant available clinical information concluded that only two of those 87 cases actually were osteonecrosis. In August 2012, the agency's Arthritis Advisory Committee lifted the clinical hold and permitted continuation of the development program of tanezumab and other nerve growth factor inhibitors.

However, on December 14, 2012, the FDA placed a new partial clinical hold on this class of medications. Victoria Davis, a spokesperson for drugmaker Pfizer, explained the situation to MedPage Today in an e-mail.

"The partial clinical hold was based on peripheral nervous system effects observed in animal studies conducted with nerve growth factor inhibitors by other companies. Current and future studies of tanezumab in cancer pain are not affected by this partial clinical hold," she wrote.

Efficacy Findings

Tanezumab is a selective mediator of the neurotrophin nerve growth factor, which has been shown in animal models to interfere with augmentation of pain signals and in previous clinical studies to improve OA pain and function.

To explore the possibility that combining tanezumab with naproxen or celecoxib would provide further benefits, Thomas J. Schnitzer, MD, PhD, of Northwestern University in Chicago, and colleagues enrolled 2,700 patients with hip or knee OA from February to December 2009.

The study was planned to last 56 weeks, with administration of intravenous tanezumab every 8 weeks, with or without 500 mg naproxen or 100 mg celecoxib twice per day. The primary endpoints were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function, and patient global assessment at week 16.

Those receiving the NSAID plus 5 mg or 10 mg tanezumab had more pronounced pain relief, with decreases of -2.13 and -2.36 points on the pain subscale, respectively (P<0.01 for both).

For patients receiving celecoxib, those given the NSAID alone had decreases of -1.47 points, while those given 5 or 10 mg of tanezumab alone had decreases of -2.02 and -2.05, respectively (P<0.01 for both).

Similar improvements were observed for the WOMAC physical function subscale, with significantly greater reductions for tanezumab alone and in combination with the NSAIDs compared with the NSAID alone.

On the third component of the primary endpoint, patient global assessment, significant improvements were seen only for the 10 mg tanezumab plus naproxen group and both tanezumab doses plus celecoxib.

Longer-term outcomes couldn't be evaluated because of the partial clinical hold, stopping the trial, and the ensuing discontinuation of almost half of the participants.

"This study highlighted the efficacy of various dose levels of tanezumab as well as the fact that the combination of an NSAID plus tanezumab was associated with an increased incidence of adverse events involving the joints, primarily manifest as a rapidly progressive form of OA," Schnitzer told MedPage Today.

Safety Details

In the study, the incidence of rapidly progressive OA was 0.7% for 5 mg of tanezumab and 1.3% for 10 mg, compared with 0.2% for the NSAIDs. The hazard ratio for 5 mg tanezumab alone versus an NSAID alone was 4.3 (95% CI 0.5-38.4, P=0.197) and for 10 mg, the HR was 7.3 (95% CI 0.9-60.1, P=0.064).

But rapidly progressive OA was more likely when tanezumab was given in combination with an NSAID, with an HR of 10.4 (95% CI 1.3-83.1, P=0.026) for 5 mg and 10.2 (95% CI 1.3-80, P=0.028) for 10 mg.

"The mechanisms responsible for rapidly progressive osteoarthritis associated with tanezumab treatment are uncertain but may result in part from reduced joint pain leading to increased joint loading and overuse and thus accelerate further damage to a susceptible joint," stated the FDA's Arthritis Advisory Committee briefing document concerning adjudication.

A total of 33 of the 87 suspected cases of osteonecrosis were patients in this study. Only one was determined to be osteonecrosis during the adjudication, and radiologic evidence suggested that it had been present for at least a year.

"Based on adjudication outcomes, including histopathology confirmation in some cases, it appears that many initial reports of osteonecrosis were based on appearance of fragments of necrotic bone due to bone failure .... These bone fragments differ histologically from bone infarction and necrosis," Schnitzer's group explained.

Another area of concern was peripheral sensory changes, which had been reported by 14% of patients receiving tanezumab in an earlier study, with some cases unresolved.

In this trial, sensory abnormalities included paresthesia, hypoesthesia, and hyperesthesia.

These events were classified as "new or worsening peripheral neuropathy" on patients' final neurologic examination in 5.7% to 6.6% of the tanezumab groups compared with 1.7% of the NSAID groups.

Most of the new or worsening sensory findings were cases of carpal tunnel syndrome rather than polyneuropathy or radiculopathy. "These results are not the expected pattern for a neurotoxic compound, which typically causes length-dependent polyneuropathy," the investigators noted.

They suggested that the appearance of a mononeuropathy in these patients may have resulted from "unmasking" with nerve growth factor inhibition.

In 2012, when the FDA lifted the initial partial clinical hold, the agency recommended additional safety measures such as avoiding combination NSAID therapy and high doses, and excluding patients with rapidly progressing disease.

Looking Ahead

"The implications of the study are that tanezumab holds promise to be an effective agent for the management of the signs and symptoms of osteoarthritis, and that there still remain a number of questions that need to be resolved, particularly in regard to joint safety," Schnitzer told MedPage Today.

"Future studies will be focused on subjects with an inadequate response who cannot tolerate or who have a contraindication for approved or standard of care therapies," he and his colleagues concluded.

"The tanezumab program currently is subject to a partial clinical hold by the FDA pending submission of additional nonclinical data," Davis stated.

"Subject to the removal of the partial clinical hold, we are planning to continue development of tanezumab for the treatment of osteoarthritis, chronic low back pain, and cancer pain. In October 2013, we entered into a collaboration agreement with Eli Lilly and Company to jointly develop and globally commercialize tanezumab for those indications," she explained.

The FDA declined to comment, saying "FDA cannot disclose information about applications under review, outside of what is discussed at an advisory committee meeting."

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